7023
J. Am. Chem. Soc. 1993, I I S , 7023-7024
Facile Intramolecular CarboUthiation Reactions of Alkylthie and Alkoxyacetylenes by Stabillzed Carbanions. A Novel Strategy for the Synthesis of Fuactioualized Carbocyclea
Scheme I
Raymond L. Funk,' Gary L. Bolton, Kay M. Brummond, Karen E. Ellestad, and John B. Stallman Department of Chemistry University of Nebraska, Lincoln Lincoln, Nebraska 68588 Department of Chemistry The Pennsylvania State University University Park, Pennsylvania I6802 Received February I I, 1993 Despite their extensive investigation, intramolecular carbolithiation reactions of alkynes have seen limited application in organic synthesis.' This situation, no doubt, reflects the necessity of generating the alkyllithium reagents (which are incompatible with many functional groups of interest)2 and using "activated" acetylenes (phenyl or trimethylsilyl) in order to effect efficient cyclization reactions. We have made the discovery, albeit serendipitously, that alkylthio- and alkoxyacetylenes smoothly participate in cyclization reactions with a variety of stabilized lithio carbanions to provide functionalized exocyclic and endocyclic enol (thioenol) ethers. We delineate, herein, the scope and limitations of this transformation and document its utility in several carbocycle annelation processes. The first cyclization reaction of this type was observed during an attempted "routine" preparation of the u-methylated sulfone 60 from sulfone 1(Scheme I). Instead of the desired compound,' a product was isolated in excellent yield (96%) whose spectral characteristics were consistent with structure Sa4 and whose structural assignment was further corroborated by hydrolysis of the enol ether moiety of Sa to the corresponding cyclopentanone. A reasonable mechanism for this transformation would involve trans-carbometalation of the alkoxyacetylene moiety of 2 by the a-phenylsulfonylanion to afford the vinyl anion 3r, equilibration to the thermodynamicallypreferred allyl/u-phenylsulfonylanion 4, and regiogpecific methylation with methyl iodide to furnish the cyclopentenyl sulfone Sa. In order to determine whether this cyclization reaction is driven by formation of the relatively stabile anion 4, the a-methylated sulfone60 was prepared (1,l equiv of BuLi, -78 "C, THF; MeI). (1) For recent examples wherein radical intermediateshave been excluded and lead- refercncca therein, see: (a) Bailey, W. F.;Ovarka, T. V.; Leipert, T. K. TerrahedronLcrr. 1989,30,3901.(b) Bailey, W. F.;Ovaska,T. V. Ibid. 1990,3I,627. (c) Ncgiahi, E.4.; Wu, G.; Cederbaum, F. E. Ibid. 1990,31, 493. For recent arbometrhtion n 0 c t i 0 ~ of alkynss by Grignard or organotitaniumreagcny see: (d) Fujikura,S.;Inoue,M.; Utimoto. K.; No&, H. Tetrahedron k r r . 1984,25, 1999. (e) Stille, J. R.;Harms, A. E. Ibid. 1992,33,6565. (2) However, intnmoldar carbometalation reactions of copper-zinc organometallicl and palladium-catalyzed cyclizations are more tolerant of functionality, see: (a) Knochel, P.;Rao, S.A. J. Am. Chem. Soc. 1991,113, 5735. (b) Crandall, J. K.; Aym, T. A. Organometalllcs 1992,11,463.(c) Monteiro, N.; Balme, G.; Gore, J. Synlett 1992,227. (d) Negishi, E.; Zhang, Y.; Wu, G.-Z.; Agnel, 0. J. Am. Chem. Soc. 1990,112,8590.(e) Trost, B. M. Ace. Chem. Res. 1990, 23, 34. (0Gore, J.; Fournet, G.; Balme, G. Tetrahedron 1991,47,6293. (3) Thii result was not totally unanticipated since we were well aware of the fact that alkyllithium reagents undergo additio&elimination reactions with allioxyacotylmea to providediubatituted acetylenes, KC: (a) Kooyman, J. G.; Hendriks, H. P. G.; Montijn, P. P.;Brand", L.; k e n s , J. F. Red. Trw. Chim. 196& 87.69. For the addition of organooopper reagents, see: (b) Normant, J. F.; Alexaldr. A.; Cahiez, G. Tetrahedron 1980,36,1961.(c) Wijkem, P.;Vermcer, P.J. Orgammer. Chem. 1986,301,247. (4)All cycliivtion products reported herein exhibit satisfactory spectral (IR, NMR), analytical and/or high-resolution mass spectral characteristics.
6a
R.E~
6b
R-
A
'
5a
J
5b bh
Nonetheless, the cyclization of 6a also proceeded smoothly (1 equiv of BuLi, -78 OC to 0 OC, T H E NHdCl), if HMPA (2 equiv) was present, to afford Sa (88%). This result suggested that the vinyl anion 3b produced in this reaction might be stable and capable of interception. However, upon warming of the reaction mixture to 0 OC and addition of methyl iodide, a 1:l mixture (86%) of Sa and the o-tolyl sulfone analogous to Sa was isolated. Apparently, deprotonation of the solvent (THF) and ortho-metalation of the phenylsulfonyl moiety is the thermodynamic driving force of this particular reaction. All subsequent efforts to trap related vinyl anion intermediates using either a tert-butyl sulfone analogous to 6a or an alkoxyacetylene capable of chelating the lithium atom of the putative vinyl anion intermediate (6a, R = C H ~ C H ~ O C H Z C H ~ O C Hhave ~ C Hbeen ~) equally unsuccessful. Finally, useful levels of relativeasymmetric induction by chiral alko~yacetylenes~ have been observed in these cyclizations. For example, the enantiomerically pure trans-2phenylcyclohexyloxyacetylene 6b gave an 89:ll mixture of diastereomers 5b (65%) and warrants further development as a novel strategy for the enantioselective synthesis of carbocycles. The regioselectivity of the cyclization reactions of alkoxyacetylene homologs of 1, as well as the analogous alkylthioacetylenes, is presented in Table I. As shown in entries a and c, the preference for nucleophilic addition at the a-carbon of the alkoxyacetylene moiety' is insufficient to overcome a kinetically favored attack at the &carbon leading to the smaller ring system. However, the preferred site of intermolecular attack by nucleophiles on thioalkoxyacetylenes is at the &carbon? and, consequently, these cyclizations are completely regioselective (entries b and a). It should be further noted that only one alkene stereoisomer was observed for each of the exo-adducts. It is presently unclear whether the (2)-olefin stereochemistrf results from an atypical trans-carbometalation' reaction or, alter( 5 ) (a) Greene, A. E.; Moyano, A,; Charbonnier, F. J. Org. Chem. 1987, 52,2919. For asymmetric Pauson-Khand cyclizations using chiral alkoxyacetylenes and enol ethers derived from them, see: (b) Greene, A. E.; Poch, M.; Valentf, E.;Moyano, A.; PericBs, M. A.; Castro, J.; DeNicola, A. Tetrahedron Lett. 1990,31,7505. (c) Castro, J.; Sirensen, H.; Riera, A,; Morin, C.; Moyano, A.; Perids, M. A. J. Am. Chem. Soc. 1990,112,9388. (6)These substrates were prepared by alkylation of ethoxyacetylene or ethylthioacetylene with the appropriate 1-bromo-w-chloroalkane(1 equiv of BuLi, 1 q u i v of dihalide, 1 cquiv of HMPA, THF, room temperature, 6 h) followed by treatment with sodium benzenesulfinate (2 equiv, DMF). (7)Viehe, H. G. Chemistry of Acetylenes; Marcel Deklrer, Inc.: New York, 1969; p 788. (8)The sterecchemical assignment for the exctadduct of entry a is based on an X-ray crystallographicanalysis. The stereochemicalassignmentfor the exctadduct of entry c is h e d on its partial isomerization (CHCI,, 7 days) to a new isomer. A 7% NOE was observed for the a-phenylsulfonyl proton resonanceupon irradiation of the olefinicproton resonanceof this new isomer, whereas irradiation of the analogous proton resonance in the original isomer gave no enhancement of the a-phenylsulfonyl proton resonance.
OOO2-7063/93/1616-7023$04.00/0 Q 1993 American Chemical Society
Communications to the Editor
1024 J. Am. Chem. SOC., Vol. I 15, No. 15, I993 Table I. Regiochemistry of Cyclizations of Alkoxy- and Thioalkoxvacetvlenes with Phenylsulfonyl Anions"
Table III. Carbocyclic Ring Annelation via Alkoxyacetylene Cyclization Reactions
alkoxyacetylene ratio entry or thioalkoxyacctylene exo-adduct enhadduct yield (%)
entry
/c&
alkoxyacetylene
intermediate adduct
product {yield, %)
S02Ph &Ph
SOpPh 75
x=o
a b
X-S
25 0
100
53 75
bpPh b
/
Ph
&S02Ph
C
x=o
d
X-S
34 0
66 100
54 57
HRop 0
* 2equivofBuLi,2equivofHMPA,THF,-78OC toroom temperature, 30 min; aqueous NH4C1.
Table II. Additional Stabilized Carbanions which Participate in Cyclizations with Alkoxyacetylenes entry alkoxyacctylene product yield (%)
b
PR
foR
OEt
~
R I 2-Phenykycbhexyl
N O C P i 3 L
C
O
P
OH
~
OEt
H
(we
~~
2 quivof BuLi, 2 equiv of HMPA, THF, -78 to0 OC, 30 min; H@+. 72b
-COpEt
d
h
2.1 equivofLDA, 5equivofHMPA,THF,-78 OCtoroomtemperature, 1 h; HpO+. 2.1 equiv of LDA, 5 q u i v of HMPA, THF, -78 to 40 OC, 3 h; H,O+. 1.1 equiv of LDA, 5 equiv of HMPA, -78 OC to room temperature, 6 h.
phorus ylides (entrya), ester enolates (entry b), and ketone enolates (entries c-e) all participate in cyclization reactions with alkoxyacetylenes. The cyclization of a cyano-stabilized carbanion analogous to the ester enolate of entry b was also successful, but the cyclization of the analogous malonate carbanion failed. It is of interest to note that the regiochemistry of the cyclization is sensitive to the degree of substitution of the ketone enolate (cf. entries d us e). The potential of this new methodology to impact on organic synthesis is clearly evident in the carbocyclic ring annelation processes enumerated in Table 111. Fused bicyclo (entries a s ) , bridged bicyclo (entry d), and spiro annelations (entry e) can be accomplished via intramolecular carbometalation reactions of various stabilized carbanions with alkoxyacetylenes. The ready accessibility of the alkoxyacetylene substrates shown in Table I11 and the polyfunctionalized products that ultimately arisefrom these reaction sequences are noteworthy features of this novel strategy for carbocycle synthesis. The further development of this new methodology and its application in natural product synthesis will be reported in due course.
f0c6Hi3 WPh R
d e
R=H
R-Me
aa
12'
19
ai
76e
a 1.1 equiv of BuLi, 2 equiv of HMPA, THF, -78 to 0 OC, 1 h; 1 equiv of 3-~yclohexcnecarboxaIdehyde,room temperature, 2 h. 1.1 equiv of LDA, 5 equiv of HMPA, THF, -78 to 0 OC, 2 h; aqueous NH4CI. 1.1 cquiv of LDA, 5 equiv of HMPA, -78 to 40 OC, 3 h; 1.5 cquiv of C&I. dMixtureof ( E ) / ( Z )stereoisomers (88:12). 1.1 equivof LDA, 5 equiv of HMPA, THF, -78 to 40 OC, 4 h; aqueous NH&1.
natively, from cis-carbometalation followed by equilibration of the intermediateallyl/a-phenylsulfonylanion,which might prefer the (2)-stereochemistry due to chelation of the lithium atom with the enol ether oxygen (sulfur) atom. The examples listed in Table I1 illustrate that this cyclization reaction is not unique to sulfone-stabilized carbanions. Phos-
Acknowledgment. We appreciatethe financialsupport provided by the National Institutes of Health (Grant No. GM28663).
Supplementary Material Available: Spectral data for all cyclization products ( 5 pages). Ordering information is given on any current masthead page.
